Use of phosphorothioate-modified oligodeoxynucleotides to inhibit NF-kappaB expression and lymphocyte function.
NF-kappaB is a potential target for immunosuppressive therapy. Two methods were evaluated to inhibit NF-kappaB: the antisense (AS) approach in which single-stranded oligodeoxynucleotides (ODNs) bind the mRNA for the RelA subunit of NF-kappaB and the transcription factor decoy (TFD) approach in which double-stranded ODNs bind the NF-kappaB protein. AS and TFD inhibited NF-kappaB binding and decreased total IgG and anti-dsDNA antibody production in splenocytes from the BXSB/Yaa autoimmune mouse strain. TNF-alpha expression was reduced by AS and TFD, as were the levels of IL-2. But AS effects did not last beyond 24 h, whereas TFD inhibited cytokine production after 72 h. AS had no effect upon IL-6, while the TFD reduced the secretion of IL-6. Therefore, the suppression of immune response mediators by AS or TFD, through inhibition of NF-kappaB, is substantial. These inhibitors can serve as novel choices for therapy in the treatment of autoimmune disorders.
Khaled
A R
AR
Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, Florida 32620, USA.
Butfiloski
E J
EJ
Sobel
E S
ES
Schiffenbauer
J
J
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007074:Immunoglobulin G / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013873:Thionucleotides / Q000494:pharmacology*; D051996:Transcription Factor RelA
D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D051996:Transcription Factor RelA